Sex steroids regulate insulin sensitivity and glucose metabolism. We had characterized a lean type 2 diabetes (T2D) rat model using gestational low-protein (LP) diet programming. Our objective was to identify if endocrine dysfunction leading to decreased sex hormone levels will precede the development of T2D and if steroid replacement will prevent the onset of the disease. Pregnant rats were fed control or isocaloric LP diet from gestational day 4 until delivery. Normal diet was given to all mothers after delivery and to pups after weaning. LP offspring developed glucose intolerance and insulin resistance at 4 months. We measured sex steroid hormone profiles and expression of key genes involved in steroidogenesis in testis and ovary. Furthermore, one-month old rats were implanted with 90-day slow release T and E2 pellets for males and females, respectively. Glucose tolerance test (GTT) and euglycemic hyperinsulinemic clamp was performed at 4 months. LP-programmed T2D males had low T levels and females had low E2 levels due to dysregulated gene expression during steroidogenesis in gonads. GTT and euglycemic hyperinsulinemic clamp showed that LP males and females were glucose intolerant and insulin resistant; however, steroid supplementation prevented the onset of glucose intolerance and insulin resistance. Rats that developed T2D by LP programming have compromised gonadal steroidogenesis leading to low T and E2 in males and females, respectively. Sex steroid supplementation prevented the onset of glucose intolerance and insulin resistance indicating low sex steroid levels could cause compromised glucose metabolism ultimately leading to T2D.

中文翻译：

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在子宫内低蛋白饮食中，成年后代的 2 型糖尿病是由大鼠的性激素介导的†。

性类固醇调节胰岛素敏感性和葡萄糖代谢。我们使用妊娠期低蛋白 (LP) 饮食计划构建了瘦 2 型糖尿病 (T2D) 大鼠模型。我们的目标是确定导致性激素水平下降的内分泌功能障碍是否会先于 T2D 的发展，以及类固醇替代是否可以预防该疾病的发作。从妊娠第 4 天直至分娩，给怀孕大鼠喂食对照或等热量 LP 饮食。分娩后所有母亲和断奶后的幼崽均给予正常饮食。LP 后代在 4 个月时出现葡萄糖不耐受和胰岛素抵抗。我们测量了睾丸和卵巢中性类固醇激素的概况以及参与类固醇生成的关键基因的表达。此外，1个月大的雄性和雌性大鼠分别植入90天缓释T和E2颗粒。4个月时进行葡萄糖耐量试验（GTT）和正常血糖高胰岛素钳夹。由于性腺类固醇生成过程中基因表达失调，LP 程序化的 T2D 男性 T 水平较低，女性 E2 水平较低。GTT和正常血糖高胰岛素钳夹显示LP男性和女性存在葡萄糖不耐受和胰岛素抵抗；然而，补充类固醇可以预防葡萄糖不耐受和胰岛素抵抗的发生。通过 LP 编程而患上 T2D 的大鼠，其性腺类固醇生成受到损害，导致雄性和雌性的 T 和 E2 分别较低。补充性类固醇可预防葡萄糖不耐受和胰岛素抵抗的发生，表明性类固醇水平低可能导致葡萄糖代谢受损，最终导致 T2D。